3-oxadiazolyl-5-aminoalkyl-beta-carboline derivatives compositions and use

ABSTRACT

Compounds of formula I ##STR1## wherein n is 0 or 1, 
     R 1  is hydrogen or lower alkyl, 
     R 2  and R 3  each independently is hydrogen, optionally substituted lower alkyl, acyl or aryl, or together with the nitrogen atom form a 5-6-member heterocycle, 
     R 4  is hydrogen, lower alkyl or lower alkoxyalkyl and 
     X is COOR 6 , CO--NR 7  R 8 , or an oxadiazolyl radical of the formula ##STR2## wherein R 5  is H, lower alkyl or cycloalkyl, 
     R 6  is H or lower alkyl, 
     R 7  and R 8  each independently is hydrogen, optionally substituted lower alkyl, acyl or aryl, or 
     R 7  and R 8  together with the nitrogen atom can form a 5-6-member heterocycle, 
     are valuable drugs, e.g., have psychotropic activity.

This is a division of application Ser. No. 944,165 filed Dec. 22, 1986now U.S. Pat. No. 4,731,365.

This invention relates to new 5-aminoalkyl-beta-carboline derivatives,their production and their use as medicines.

The compounds according to the invention have valuable pharmacologicalproperties. They particularly affect the central nervous system and thusare suitable as psychotropic drugs.

The compounds according to the invention have the general formula I##STR3## wherein n is 0 or 1,

R¹ is hydrogen or lower alkyl,

R² and R³ each independently is hydrogen, optionally substituted loweralkyl, acyl or aryl, or together with the nitrogen atom form a5-6-member heterocycle,

R⁴ is hydrogen, lower alkyl or lower alkoxyalkyl and

X is COOR⁶, CO--NR⁷ R⁸, or an oxadiazolyl radical of the formula##STR4## wherein R⁵ is H, lower alkyl or cycloalkyl,

R⁶ is H or lower alkyl,

R⁷ and R⁸ each independently is hydrogen, optionally substituted loweralkyl, acyl or aryl, or

R⁷ and R⁸ together with the nitrogen atom can form a 5-6-memberheterocycle.

Lower alkyl includes both straight-chain and branched radicals of C₁ -C₆carbon atoms. For example, preferred C₁₋₄ alkyl radicals are methyl,ethyl, n-propyl, isopropyl, n-butyl,isobutyl and tert-butyl. Pentyl andhexyl radicals are also suitable.

Suitable substitutents on the lower alkyl radicals R², R³, R⁷ and R⁸include: hydroxy, lower alkoxy, mercapto, lower alkylthio, phenyl, aminooptionally substituted by lower alkyl or a nitrogen-containing5-6-member heterocycle (e.g., saturated or unsaturated aliphatic) whichalso can contain another heteroatom such as sulfur, nitrogen or oxygen,for example, morpholine, piperidine, thiomorpholine, piperazine,pyrrolidine and can be substituted with 1 or 2 lower alkyl groups. Inthe piperazine radical the nitrogen in the 4-position additionally canbe substituted by a lower alkyl radical. Above and below, "lower" refersto 1-6 carbon atoms.

If R² and R³ or R⁷ and R⁸ together with the nitrogen atom form aheterocycle, then the latter is 5-6-membered and can be saturated orunsaturated, e.g., aliphaic or aromatic, and can contain anotherheteroatom such as sulfur, nitrogen or oxygen. For example, theabove-named saturated heterocycles and the following unsaturatedheterocycles are suitable: imidazole, pyrazole, pyrrole, etc.

The acyl radicals preferably are alkanoyl derived from an aliphaticcarboxylic acid with up to 4 carbon atoms, for example, acetic acid,propionic acid, butyric acid, formic acid, etc.

Aryl includes phenyl and heteroaromatic rings, for example, furan,thiophene, pyridine, etc., e.g., 5 or 6 membered rings containing 1-2 O,N or S atoms.

Lower alkoxyalkyl R⁴ groups include C₁₋₆ -alkoxy-C₁₋₆ -alkyl, where bothalkyl portions can be derived from groups such as those mentioned above.

Preferred R⁷ and R⁸ groups are C₁₋₃ alkyls and 5-6-membernitrogen-containing saturated heterocyclic groups formed together withthe nitrogen atom and which can contain another heteroatom.

Cycloalkyl radicals R⁵ can contain 3-7 carbon atoms. Preferred are thosewith 3-5 carbon atoms, for example, cyclopropyl, methylcyclopropyl,cyclobutyl, cyclopentyl, etc.

It is known that certain sites in the central nervous system ofvertebrates exhibit a great specific affinity for the binding of 1,4-and 1,5-benzodiazepines (Squires, R. F. and Braestrup, C., Nature(London) 266 (1977) 734). These sites are called benzodiazepinereceptors. The important receptor affinity for the pharmacologicalproperties of the compounds according to the invention was determined byexamination of their capability to displace radioactively markedflunitrazepam from benzodiazepine receptors. The displacement activityof the compounds according to the invention is indicated as IC₅₀ andED₅₀ values. The IC₅₀ value indicates the concentration which causes a50% displacement of the specific binding of H³ -flunitrazepam (1.0 nM,0° C.) in samples with a total volume of 0.55 ml of a suspension ofbrain membranes, e.g., of rats.

The displacement test is performed as follows:

0.5 ml of a suspension of untreated rat forebrain in 25 mM KH₂ PO₄,pH=7.1 (5-10 mg of tissue/sample) is incubated for 40-60 minutes at 0°C. together with ³ H-diazepam (specific activity 14.4 Ci/mmol, 1.9 nM)or ³ H-flunitrazepam (specific activity 87 Ci/mmol, 1.0 nM). Afterincubation, the suspension is filtered through a glass filter, theresidue is washed twice with cold buffer solution and the radioactivityis measured with a scintillation counter.

The test is then repeated, but, before addition of the radioactivelymarked benzodiazepine, a specific amount or an excess amount of thecompound whose displacement activity is to be determined, is added. TheIC₅₀ value can be calculated on the basis of the values obtained.

The ED₅₀ value represents the dose of a test substance which causes areduction of the specific binding of the flunitrazepam on thebenzodiazepine receptor in a live brain to 50% of the control value.

The in vivo test is performed as follows:

The test substance is injected into groups of mice in different dosesand normally intraperitoneally. After 15 minutes the ³ H-flunitrazepamis administered intravenously to the mice. After another 20 minutes themice are sacrificed, their forebrain is removed and the radioactivityspecifically linked to the brain membrane is measured by scintillationcounting. The ED₅₀ value is determined from the dose/action curves.

In the pharmacological tests, the compounds according to the inventionshow especially anxiolytic and anticonvulsive effectiveness. Forexamination of the anticonvulsive action, stopping of the spasms inducedby pentylenetetrazole (pentazol) was studied. Pentazol is administeredsubcutaneously in an amount of 150 mg/kg as a hydrochloric acid solution(pH 2-3) 15-30 minutes after the intraperitoneal application of the testsubstance. This amount induces clonic and tonic spasms, which lead todeath in untreated animals. The number of mice which show spasms and thenumber of them that died 30 minutes after pentazol are recorded. TheED₅₀ values are determined according to the method of Litchfield andWilcoxon (J. Pharmacol. exp. Ther. 96 (1949) 99-103) as the amount ofantagonistically acting substance which protects 50% of the animals fromspasms and death.

The new compounds of general formula I have valuable pharmacologicalproperties. They particularly affect the central nervous system and thusare suitable as psychotropic drugs for human medicine. The compounds canbe used especially for treatment of anxiety, either alone or accompaniedby depressions, epilepsy, sleep disturbances, spasticities and musclerelaxation during anesthesia. Some compounds according to the inventionalso show amnestic properties and others memory-promoting properties.

The compounds according to the invention can be used for the formulationof pharmaceutical preparations for administration, e.g., to mammalsincluding humans, for example, for oral and parenteral applicationaccording to galenic methods known in the art.

Suitable inactive ingredients for formulation of pharmaceuticalpreparations include those physiologically compatible organic andinorganic vehicles for enteral and parenteral application, which areinert in regard to the compounds according to the invention. Suitablevehicles include, for example, water, salt solutions, alcohols,polyethylene glycols, polyhydroxyethoxylated castor oil, gelatins,lactose, amylose, magnesium stearate, talc, silicic acid, fatty acidmono and diglycerides, pentaerythritol fatty acid ester,hydroxymethylcellulose and polyvinylpyrrolidone. The pharmaceuticalpreparations can be sterilized and/or mixed with inactive ingredientssuch as lubricants, preservatives, stabilizers, wetting agents,emulsifiers, buffering agents and dyes. For parenteral application aresuitable especially injection solutions or suspensions, especiallyaqueous solutions of the active compounds in polyhydroxyethoxylatedcastor oil. For oral application are suitable especially tablets,sugar-coated tablets or capsules with talc and/or a hydrocarbon vehicleor binding agent, such as, for example lactose, corn or potato starch.The administration can take place also in liquid form, as, for example,as juice to which optionally a sweetening agent is added.

The compounds according to the invention can be administered in a doseunit of 0.05 to 100 mg of active substance in a physiologicallycompatible vehicle. The compounds according to the invention areadministered in a dose of 0.1 to 300 mg/day, preferably 1-30 mg/day,e.g., as an anxiolytic, analogously to the known agent diazepam andanalogously to clonazepam to treat epilepsy.

The production of the compounds of general formula I takes placeaccording to methods known in the art.

For example, the production of the compounds of formula I can beachieved by

(a) reacting a compound of formula II ##STR5## wherein R¹, R⁴, X and nhave the meanings indicated above,

Z is halogen or hydroxy and

R⁹ is hydrogen or a protecting group, with a compound HNR² R³, whereinR² and R³ have the meanings indicated above,

and then optionally cleaving off the protecting group,

(b) hydrogenating a compound of formula III ##STR6## wherein R⁴ and Xhave the meanings mentioned above and

Y is an O₂ N--C--R¹ -- or R² N group, wherein R¹ has the meaningsmentioned above and R² represents optionally substituted lower alkyl oraryl,

to a compound of formula I with R³ being hydrogen.

Then, optionally, the compounds obtained according to process (a) or (b)can be transesterified or the ester saponified. Optionally, thecarboxylic acid thus obtained is

(α) amidated or

(β) reacted with a compound ##STR7## wherein R⁵ has the meaningsmentioned above, to form a compound of formula I in which X is ##STR8##with R⁵ having the meanings mentioned above, or

(c) reacting a compound of formula IV ##STR9## wherein R¹, R², R³, R⁴and n have the meanings mentioned above,

with a carboxylic acid anhydride (R⁵ CO)₂ O, wherein R⁵ has the meaningmentioned above, to form a compound of formula I in which X is ##STR10##with R⁵ having the meanings mentioned above.

Introduction of the amino group according to process (a) can, forexample, take place by reaction of the corresponding halogen compoundwith primary or secondary amines. Chlorine, bromine or iodine issuitable as halogen. Suitable as solvents are dipolar aprotic solvents,for example, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone,etc., or protic solvents, for example, alcohols such asmethanol,ethanol, propanol, etc. or chlorinated hydrocarbons, forexample, chloroform, methylene chloride, etc.

Starting from hydroxyalkylene compounds, the corresponding amines canlikewise be produced according to the usual methods, for example, byhaloalkylene compounds produced intermediately with phosphoroustrihalide in the above-mentioned solvents.

Suitable reaction temperatures are from 0° C. to the boiling temperatureof the solvent. The reaction is generally ended after about 10 to 24hours.

If a usual protecting group as, for example, an acyl or tosyl protectinggroup is present in the 9 position, the group is cleaved off in thereaction with the amine or subsequently removed by the usual methods,for example, by treatment with bases such as sodium or potassiumcarbonates/hydroxides or alcoholates.

The amination can be performed with or without a protective inert gas,such as argon or nitrogen.

If in process (a) beta-carboline-3-carboxylic acids are used, thecorresponding beta-carboline-3-carboxylic acid amides are obtained.

Hydrogenation of the compounds of formula III according to process (b)takes place preferably catalytically, for example, with noble metalcatalysts such as platinum or palladium on suitable supports such ascarbon or with Raney nickel. Hydrogenation is preferably performed inprotic solvents such as alcohols, for example, ethanol, methanol,propanol, etc. at room temperature to the boiling temperature of thesolvent under normal pressure or H₂ pressure.

To avoid transesterification, the operation is performed in therespective alcohol of the ester component as solvent. The reaction isgenerally ended after 5 to 7 hours.

According to process (b) primary amines are obtained by hydrogenation ofnitro compounds, and secondary amines are obtained by hydrogenation ofimines.

If a transesterification is desired, it is possible to react, forexample, with the corresponding alcohol or alkali alcoholate.Optionally, titanium tetraisopropylate can be added in water-freealcohol as catalyst. The transesterification usually is performed attemperatures of 60°-120° C. and is ended after about 2-6 hours.

Introduction of the tert-butyl ester group takes place, for example, byreaction of the carboxylic acid withtert-butoxy-bis-(dimethyl-amino)methane. The reaction is generallyperformed under an inert gas atmosphere such as argon or nitrogen andwith exclusion of moisture at elevated temperature.

The saponification of the ester group can take place in an acidic oralkaline manner; preferably it is saponified in an alkaline manner, bythe ester being heated to temperatures up to the reflux temperature ofthe reaction mixture with dilute aqueous lye such as potassium or sodiumhydroxide in a protic solvent such as, for example, methanol, ethanol orethylene glycol.

Carboxylic acid amides are obtained, for example, by reaction withamines of the corresponding imidazolides, which are intermediatelyproduced from carboxylic acids and carbonyldiimidazole orthionyldiimidazole. The reaction is performed at room temperature indipolar aprotic solvents, for example, dimethylformamide,dimethylacetamide, etc.

For the introduction of the 1,2,4-oxadiazol-5-yl radical thebeta-carboline carboxylic acid is brought to condensation, at the refluxtemperature of the reaction mixture, with an amidoxime of the formula

    R.sup.5 --C(═NOH)NH.sub.2

in an inert solvent which boils above 100° C. and is inert in regard tothe reactant. Suitable solvents for the condensation reaction are, forexample, toluene and dimethylformamide. Appropriately, the freebeta-carboline-3-carboxylic acid is suitably activated before thecondensation reaction. For this purpose, the free acid can be converted,for example, into the mixed anhydride, into the activated ester or intothe chloride. Activation by conversion to an imidazolide withimidazole/thionyl chloride or also carbonyldiimidazole in an aproticsolvent such as dioxane, tetrahydrofuran, dimethylformamide orN-methylpyrrolidone at temperatures between 0° and 50° C., preferablyroom temperature, has proved successful.

For the introduction of the 1,2,4-oxadiazol-3-yl radical, for example,the beta-carboline-3-carboxamidoxime of formula IV is reacted with theacid anhydride (R⁵ CO)₂ O at room temperature and then heated toboiling. The reaction is ended after about 7 hours and working up isdone according to the usual processes.

The compounds according to the invention can be present racemates or canbe separated into their antipodes by the usual processes.

The starting materials are known or can be prepared from known startingmaterials according to known processes. For example, 3-carboxamidoximescan be produced from beta-carboline carboxylic acids by reacting3-carboxylic acid nitrile with hydroxylamine. The 5-halomethyl initialcompounds of formula II can be prepared, for example, by reaction of5-methyl carboline compounds with N-halosuccinimide, especiallyN-bromosuccinimide under the usual reaction conditions.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the preceding text and the following examples, all temperatures areset forth uncorrected in degrees Celsius and all parts and percentagesare by weight, unless otherwise indicated.

EXAMPLES EXAMPLE 1 5-Phenylaminomethyl-beta-carboline-3-carboxylic acidethyl ester

5-phenyl-iminomethyl-beta-carboline-3-carboxylic acid ethyl ester (0.25g) is hydrogenated in 100 ml of ethanol with addition of Raney nickel atnormal pressure and a temperature of 25° C. Taking up of 1 mol ofhydrogen takes about 40 minutes. The residue remaining after filteringof the catalyst and evaporation of the filtrate is chromatographed onsilica gel with a mixture of 10 parts of dichloromethane and one part ofethanol. Thus, 0.15 g of phenylaminomethyl-beta-carboline-3-carboxylicacid ethyl ester is obtained.

Melting point 256°-258° C.

The initial product is prepared as follows:

(a) 5-Formyl-beta-carboline-3-carboxylic acid ethyl ester

5-Hydroxymethyl-beta-carboline-3-carboxylic acid ethyl ester (1.0 g) isstirred in dichloromethane (250 ml) with manganese dioxide (1.5 g) for16 hours at room temperature (25° C.). After addition of more manganesedioxide (0.75 g) the reaction mixture is stirred for another 16 hours.Then after filtering of the undissolved portion it is evaporated, theresidue is recrystallized twice from ethyl acetate. Thus, 0.5 g of5-formyl-beta-carboline-3-carboxylic acid ethyl ester with a meltingpoint of 273°-276° C. is obtained.

(b) 5-Phenyliminomethyl-beta-carboline-3-carboxylic acid ethyl ester

5-Formyl-beta-carboline-3-carboxylic acid ethyl ester (0.153 g) isstirred with aniline (0.112 g) in acetic acid (3 ml) under nitrogen foran hour at 25° C. The precipitated crystals are suctioned off. The yieldis 0.111 g of 5-phenyliminomethyl-beta-carboline-3-carboxylic acid ethylester with a melting point of 298°-302° C.

EXAMPLE 25-(1-Imidazolylmethyl)-4-methoxymethyl-beta-carboline-3-carboxylic acidethyl ester

5-Bromo-methyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethylester (0.35 g) is left with imidazole (0.13 g) in dimethyl sulfoxide (4ml) for three days at room temperature. The precipitate resulting afteraddition of water (40 ml) is recrystallized from ethanol andchromatographed on silica gel with a mixture of 19 parts ofdichloromethane and one part of methanol. Thus 0.2 g of5-(1-imidazolylmethyl)-4-methoxymethyl-beta-carboline-3-carboxylic acidethyl ester with a melting point of 220°-222° C. is obtained.

The initial material is produced as follows:

(a) 4-Acetoxymethylindol e

4-Hydroxymethylindole (17 g) is heated in pyridine (12 ml) with aceticanhydride (11.9 ml) for three hours on the steam bath. After dilutionwith ether, the reaction mixture is first shaken out with 1Nhydrochloric acid, then with saturated sodium bicarbonate solution andfinally with water. The ether solution is evaporated. 20 g of4-acetoxymethylindole remains.

(b) 3-(4-Acetoxymethylindol-3-yl)-4-methoxy-2-nitrobutyric acid ethylester

4-Acetoxymethylindole (189 g) is dissolved in a mixture of toluene (6 l)and acetic acid (0.7 l). To this solution is added3-hydroxy-2-nitro-5-oxa-hexanoic acid ethyl ester (570 ml). The flaskcontaining the mixture is evacuated by means of a water jet pump. Thenbalancing to normal pressure is brought about by argon. Evacuation andpressure balancing are repeated four times. Then the reaction mixture isrefluxed for two hours in a water-free argon atmosphere. Afterconcentrating to 2 l the solution is diluted with ethyl acetate andshaken out three times with a liter of 1N hydrochloric acid each. Thenit is washed to neutrality with saturated hydrochloric acid solution.The solution, dried over sodium sulfate, is evaporated. The residue ischromatographed on silica gel with dichloromethane. 393 g of the titlecompound is obtained in oily form.

(c) 3-(4-Acetoxymethylindol-3-yl)-2-amino-4-methoxy-butyric acid ethylester

3-(4-acetoxymethylindol-3-yl)-2-nitro-4-methoxy-butyric acid ethyl ester(226 g) is hydrogenated in ethanol (2.3 l) with Raney nickel as catalystunder hydrogen of normal pressure without addition of heat. 3 mol ofhydrogen is taken up in 31/2 hours, whereby the temperature reaches amaximum of 45° C. After filtering of the catalyst and evaporation of theresidue, the raw product is chromatographed on silica gel with a mixtureof dichloromethane (97.5%) and ethanol (2.5%). 130 g of the titlecompound as noncrystalline diastereomeric mixture is obtained.

(d)5-Acetoxymethyl-4-methoxymethyl-1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylicacid-3 ethyl ester

A solution of 3-(4-acetoxymethylindol-3-yl)-2-amino-4-methoxy-butyricacid ethyl ester (8.7 g) in ethyl acetate (40 ml) is slowly added dropby drop to a solution of glyoxylic acid monohydrate (2.4 g) in water (30ml), cooled to 0° C., under argon protection and with stirring. The pHof the solution is adjusted to 4 by addition of potassium carbonate(about 1 g). Then the mixture is stirred for 2 hours, whereby it isallowed to warm to room temperature. Ethyl acetate and water phases areseparated, the water phase is shaken out three times with ethyl acetate.The combined ethyl acetate extracts, for their part, are washed oncewith water, dried with sodium sulfate and evaporated. 9 g of the titlecompound remains.

(e) 5-Acetoxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acidethyl ester

90% Azodicarboxylic acid diethyl ester (76 ml) without addition of heatwith stirring is added drop by drop to a solution of5-acetoxymethyl-4-methoxymethyl-1,2,3,4-tetrahydro-beta-carboline-1,3-dicarboxylicacid-3-ethyl ester (75 g) in oxygen-free dichloromethane (0.6 l) underargon protection. The temperature rises about 10° C. Reflux is performedfor about 9 hours, then the mixture is left at room temperature for 60hours. The precipitate is suctioned off, further end product can beobtained from the evaporated mother liquor after chromatography onsilica gel with a mixture of dichloromethane (95%) with methanol (5%).Altogether 65 g of the title compound in the form of colorless crystalswith a melting point of 129°-133° C. is obtained.

(f) 5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acidethyl ester

5-Acetoxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethylester (7.9 g) is taken up in a solution of sodium (1.4 g) in ethanol(100 ml) and left for 4 days at +4° C. The solution is concentrated,taken up in abundant ethyl acetate, washed alkali-free with water, driedwith sodium sulfate and evaporated in a vacuum. By treatment withethanol the residue yields 6.6 g of the title compound as colorlesscrystals with a melting point of 139°-140° C.

(g) 5-Bromo-methyl-4-methoxymethyl-beta-carboline-3-carboxylic acidethyl ester

5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethylester (1 g) is dissolved in dichloromethane (50 ml). In a dry argonatmosphere a solution of phosphorous tribromide (0.86 g) indichloromethane (50 ml) is added drop by drop. After 20 hours ofstirring at room temperature the resulting precipitate is suctioned offand washed with ethyl acetate. 1.2 g of the title compound, with amelting point of 223°-225° C., is obtained.

EXAMPLE 34-Methoxymethyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acidethyl ester

5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethylester (0.20 g) is dissolved in dichloromethane (5 ml). A solution ofphosphorous tribromide (0.17 g) in dichloromethane (3 ml) is added dropby drop with stirring. After three hours of stirring, the mixture iscooled to +10° C. and mixed with a solution of morpholine (1.0 ml) inethanol (5 ml) drop by drop. After standing overnight the solvent isevaporated, the residue is chromatographed on silica gel with a mixtureof dichloromethane (19 parts) and ethanol (1 part) and the titlecompound (0.16 g) with a melting point of 195°-196° C. is obtained.

Analogously there is obtained:

4-methoxymethyl-5-(4-methyl-1-piperazinylmethyl)-beta-carboline-3-carboxylicacid ethyl ester, melting point 249°-252° C.

4-methoxymethyl-5-(1-piperidinylmethyl)-beta-carboline-3-carboxylic acidethyl ester

4-methoxymethyl-5-(2,6-dimethyl-4-morpholinylmethyl)-beta-carboline-3-carboxylicacid ethyl ester

4-methoxymethyl-5-diethylaminomethyl-beta-carboline-3-carboxylic acidethyl ester

4-methyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acid ethylester

melting point 226°-227° C.

4-methoxymethyl-5-dimethylaminomethyl-beta-carboline-3-carboxylic acidethyl ester

4-methoxymethyl-5-[2-(4-morpholinyl)-ethyl]-aminomethyl-beta-carboline-3-carboxylicacid ethyl ester

5-[N-(2-ethoxyethyl)-aminomethyl]-4-methoxymethyl-beta-carboline-3-carboxylicacid ethyl ester

melting point 193°-195° C.

5-[N,N-bis(2-methoxyethyl)-aminomethyl]-4-methoxymethyl-beta-carboline-3-carboxylicacid ethyl ester

melting point 103°-105° C.

EXAMPLE 44-Methoxymethyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acid

The ethyl ester (0.30 g) obtained according to example 3 is refluxed inethanol (30 ml) with 1N of sodium hydroxide solution (2.3 ml) for 4hours. After cooling, 1N of acetic acid (2.3 ml) is added andevaporated. The crystalline evaporation residue is suctioned off andwashed well with water. Thus, 0.27 g of the title compound is obtained.

Melting point 253°-255° C.

Analogously there is produced:

4-methoxymethyl-5-(2,6-dimethyl-4-morpholinyl-methyl)-beta-carboline-3-carboxylicacid.

EXAMPLE 54-Methoxymethyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acidtert-butyl ester

The acid (0.35 g) obtained according to example 4 is heated intert-butoxy-bis-(dimethylamino)-methane (7 ml) under argon protectionfor two hours to 120° C. After evaporation of thetert-butoxy-bis-(dimethylamino)-methane the residue is taken up in ethylacetate. The solution is shaken out with saturated hydrochloric acidsolution, dried and evaporated. The residue is chromatographed on silicagel with a mixture of equal parts of hexane and acetone. The yield oftitle compound is 0.2 g.

Analogously there is obtained:

4-Methoxymethyl-5-(2,6-dimethyl-4-morpholinyl-methyl)-beta-carboline-3-carboxylicacid tert-butyl ester.

EXAMPLE 64-Methoxymethyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acidisopropyl ester

5-Bromo-methyl-4-methoxymethyl-beta-carboline-3-carboxylic acidisopropyl ester (0.53 g) is suspended in ethanol (10 ml). The solutionoccurring after addition of morpholine (2.6 ml) is allowed to stand for20 hours at 25° C. Then it is diluted with ethyl acetate (60 ml) andshaken out with water, until it no longer reacts in an alkaline manner.The neutral solution is evaporated in a vacuum, the residue isrecrystallized from ethyl acetate. The yield is 0.16 g with a meltingpoint of 214°-216° C.

The initial material is prepared as follows:

(a) 5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acidisopropyl ester

5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethylester (7.27 g) is refluxed in isopropanol (1000 ml) with titaniumtetraisopropylate (7.1 ml) for 5 hours. The solution is evaporated, theresidue is dissolved in ethyl acetate. The complete solution is reachedby addition of 1N hydrochloric acid. Then it is made alkaline byaddition of 1N sodium hydroxide solution. A precipitate resultingthereby is suctioned off. The filtrate is evaporated and yields aresidue of 6.0 g of the title compound.

4-Methyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acidisopropyl ester is analogously obtained from4-methyl-5-(4-morpholinylmethyl)-beta-carboline-3-carboxylic acid ethylester.

(b) 5-Bromomethyl-4-methoxymethyl-beta-carboline-3-carboxylic acidisopropyl ester

5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acidisopropyl ester (1.0 g) is dissolved in dichloromethane. A solution of0.83 phosphorous tribromide in 10 ml of dichloromethane is added. After20 hours the resulting precipitate is suctioned off. The yield is 1.0 gof yellow crystals with indeterminate melting point.

Analogously there are produced:

4-Methoxymethyl-5-(1-pyrrolidinylmethyl)-beta-carboline-3-carboxylicacid isopropyl ester, melting point 173°-174° C.

4-Methoxymethyl-5-(4-thiomorpholinylmethyl)-beta-carboline-3-carboxylicacid isopropyl ester, melting point 217°-219° C.

4-Methoxymethyl-5-(2,6-dimethyl-4-morpholinylmethyl)-beta-carboline-3-carboxylicacid isopropyl ester

EXAMPLE 7 5-morpholino-methyl-beta-carboline-3-carboxylic acid ethylester

Under nitrogen, a solution of 0.19 g of9-acetyl-5-bromoethyl-beta-carboline-3-carboxylic acid ethyl ester in 5ml of ethanol is mixed with 1 ml of morpholine and stirred overnight atroom temperature. After addition of water the crystallizate is suctionedoff and recrystallized from ethanol/diethylether. 0.11 g (64%) isobtained. Melting point 285° C.

The initial material is produced in the following way:

A suspension of 6.2 g of 9-acetyl-5-methyl-beta-carboline-3-carboxylicacid ethyl ester (obtained in the usual way from5-methyl-beta-carboline-3-carboxylic acid ethyl ester by the action ofacetic anhydride in pyridine) in 550 ml of carbon tetrachloride is mixedwith 4.5 g of N-bromosuccinimide and 0.17 g of azobis(isobutyro)nitrileand radiated with a 500-watt lamp (Nitraphot BT, Osram) for 2 hours,whereby the mixture boils. It is filtered hot and the filtrate isconcentrated. The raw product is recrystallized twice from carbontetrachloride. 5.9 g (75%) of the 5-bromoethyl derivative is obtained.

Melting point 193° C.

Analogously to example 7 there are produced:

5-(4-methylpiperazinylmethyl)-beta-carboline-3-carboxylic acid ethylester, melting point 287° C.

5-[N-(1-phenylethyl)-aminomethyl[-beta-carboline-3-carboxylic acid ethylester, melting point 232° C.

Analogously to example 7, but in dimethyl sulfoxide as solvent, there isobtained with imidazole:

9-acetyl-5-(1-imidazolylmethyl)-beta-carboline-3-carboxylic acid ethylester, melting point 195° C.

EXAMPLE 8 5-(1-Imidazolylmethyl)-beta-carboline-3-carboxylic acid ethylester

A suspension of 0.11 g of9-acetyl-5-(1-imidazolylmethyl)-beta-carboline-3-carboxylic acid ethylester in 5 ml of ethanol is mixed with 10 mg of K₂ CO₃ and refluxed fortwo hours. After filtering, the solution is concentrated in a vacuum,the residue is mixed with water, suctioned off and recrystallized fromwater. Yield 70 mg (71%).

Melting point 248° C.

EXAMPLE 9 5-(2-Aminoethyl)-4-methyl-beta-carboline-3-carboxylic acidethyl ester

5-(2-Nitrovinyl)-4-methyl-beta-carboline-3-carboxylic acid ethyl ester(1 g) is dissolved in ethanol (20 ml) and in a hydrogen atmosphere withstirring is slowly added drop by drop to a suspension of 10% palladiumcarbon (0.25 g) in ethanol (50 ml) and sulfuric acid (0.1 ml). In theend, it is stirred for another half hour more. Then the catalyst issuctioned off and the filtrate evaporated. After the usual working up,0.6 g of the title compound is obtained.

The initial compound is prepared as follows:

(a) 5-Formyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester

The synthesis takes place according to the method described in example 1from 5-hydroxymethyl-4-methyl-beta-carboline-3-carboxylic acid ethylester, which in turn is prepared according to example 2 from2-nitro-3-hydroxybutyric acid ethyl ester in 5 stages.

(b) 5-(2-Nitrovinyl)-4-methyl-beta-carboline-3-carboxylic acid ethylester

A solution of 5-formyl-4-methyl-beta-carboline-3-carboxylic acid ethylester (10 g), nitromethane (2 ml) and methylamine hydrochloride (0.2 g)in ethanol (50 ml) is mixed with sodium carbonate (0.3 g) and left for 5days at 20° C. with occasional shaking. Then it is evaporated tobeginning crystallization. 5 g of the title compound crystallizes fromthe solution cooled with ice water.

EXAMPLE 10 5-(2-aminopropyl)-4-methyl-beta-carboline-3-carboxylic acidethyl ester

The production takes places analogously to example 9 by condensation of5-formyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester withnitroethane and hydrogenation of the resulting4-methyl-5-(2-nitropropenyl)beta-carboline-3-carboxylic acid ethylester.

EXAMPLE 114-Methoxymethyl-5-morpholinomethyl-3-(3-ethyl,1,2,4-oxadiazol-5-yl)-beta-carboline

A solution of 0.36 g of4-methoxymethyl-5-morpholinomethyl-beta-carboline-3-carboxylic acid(prepared according to example 4) in 10 ml of absolute dimethylformamideis mixed with 0.2 g of carbonyldiimidazole and stirred for 30 minutes at60° C. Then 0.4 g of propioamidoxime in 2 ml of DMF is added and thereaction mixture heated to 100° C. for 3 hours. After distilling off ofthe solvent in a vacuum, the residue is mixed with 20 ml of xylene andrefluxed for 3 hours on the water separator, the reaction mixture isfiltered hot, the filtrate is concentrated and chromatographed on silicagel. 0.25 g (60%) of oxadiazole derivative is obtained. Melting point161°-163° C.

4-Methyl-5-(4-morpholinylmethyl)-3-(3-ethyl-1,2,4-(oxadiazol-5-yl)-beta-carboline

4-Methyl-5-(4-morpholinylmethyl-beta-carboline-3-carboxylic acidhydrochloride (0.46 g) is suspended in dimethylformamide (35 ml) andmixed with carbonyldiimidazole (0.46 g). Propionamidoxime (0.5 g) isadded to the clear solution after 24 hours at room temperature. Thedimethylformamide is distilled off in a vacuum after 48 hours at roomtemperature. The remaining oil is refluxed in xylene (50 ml) for 3 hourson the water separator, then the xylene is decanted and evaporated. Theresidue is recrystallized from ethyl acetate.

Yield 0.3 g. Melting point 189°-190° C. The initial material is producedin the following way:

A solution of4-methyl-5-(4-morpholinylmethyl-beta-carboline-3-carboxylic acid ethylester (0.5 g) in ethanol (40 ml) and 1N sodium hydroxide solution (4.3ml) is refluxed for 4 hours. After cooling, 1N hydrochloric acid (8.7ml) is added. The solution, clarified by filtering, is left for 2 daysat +4° C., then the precipitate resulting during this time is suctionedoff. The yield is 0.47 g. Melting point 270°-273° C.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make numerous changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A 5-Aminoalkyl-beta-carboline of the formula##STR11## wherein n is 0 or 1,R¹ is hydrogen or lower alkyl, R² and R³each independently is hydrogen; alkyl; alkyl substituted by OH, loweralkoxy, mercapto, lower alkylthio, phenyl, amino, amino substituted bylower alkyl or a 5-6-member aliphatic N-containing heterocycle which cancontain an additional O, N or S atom and can be substituted by 1 or 2lower alkyl groups; alkanoyl; phenyl; or a 5-6-member aromaticheterocycle containing 1 or 2 O, N or S atoms; or together with theadjoining N-atom R² and R³ form a 5-6-member aliphatic N-containingheterocycle which can contain an additional O, N or S atom and can besubstituted by 1 or 2 lower alkyl groups, R⁴ is hydrogen, lower alkyl orlower alkoxy-lower-alkyl and X is an oxadiazolyl group of the formula##STR12## wherein R⁵ is H, lower alkyl or C₃₋₇ -cycloalkyl, and "lower"refers to 1-6 carbon atoms.
 2. A compound of claim 1 wherein R² and R³together with the N-atom form said heterocycle.
 3. A compound of claim 1wherein R² and R³ form morpholino or morpholino substituted by alkyl. 4.A compound of claim 1 wherein R² and R³ are alkyl or H. 5.4-methoxymethyl-5-morpholinomethyl-3-(3-ethyl-1,2,4-oxadiazol-5-yl)-beta-carboline.6. A pharmaceutical composition comprising an amount of a compound ofclaim 1 and a pharmaceutically acceptable carrier.
 7. A composition ofclaim 6 wherein the amount of said compound is 0.05 to 100 mg.
 8. Amethod of achieving an anxiolytic effect comprising administering to apatient an amount of a compound of claim
 1. 9. A method of achieving ananticonvulsive effect comprising administering to a patient an amount ofa compound of claim 1.